on 26-Feb-2021 (Fri)

Although hypokalemia can be transiently induced by the entry of potassium into the cells, most cases result from unreplenished gastrointestinal or urinary losses due, for example, to vomiting, diarrhea, or diuretic therapy

Potassium is given cautiously in redistributive hypokalemia since the hypokalemia is transient and the administration of potassium can lead to rebound hyperkalemia when the underlying process is corrected and potassium moves back out of the cells.

It is also warranted for acute therapy in disorders such as hypokalemic or thyrotoxic periodic paralysis in which the hypokalemia is due to redistribution of potassium into the cells, often in association with significant symptoms

The severity of the manifestations of hypokalemia tends to be proportionate to the degree and duration of the reduction in serum potassium. Symptoms generally do not become manifest until the serum potassium is below 3.0 mEq/L, unless the serum potassium falls rapidly or the patient has a potentiating factor, such as a predisposition to arrhythmia due to the use of digitalis. Symptoms usually resolve with correction of the hypokalemia.

Muscle weakness usually does not occur at serum potassium concentrations above 2.5 mEq/L if the hypokalemia develops slowly [2]. However, significant muscle weakness can occur at serum potassium concentrations below 2.5 mEq/L or at higher values with hypokalemia of acute onset, as occurs in hypokalemic or thyrotoxic periodic paralysis. In addition, the pathophysiology of weakness in these disorders is more complex.

The pattern of weakness in hypokalemia is similar to that associated with hyperkalemia. Weakness usually begins in the lower extremities, progresses to the trunk and upper extremities, and can worsen to the point of paralysis.

In addition to causing muscle weakness, severe potassium depletion (serum potassium less than 2.5 mEq/L) can lead to muscle cramps, rhabdomyolysis, and myoglobinuria [4-7]. Potassium release from muscle cells during exercise normally mediates vasodilation and an appropriate increase in muscle blood flow [8]. Decreased potassium release due to profound hypokalemia can diminish blood flow to muscles during exertion, leading to ischemic rhabdomyolysis [8]. The clinical and pathologic abnormalities are reversible with potassium repletion [4]. A potential diagnostic problem is that the release of potassium from the cells with rhabdomyolysis can mask the severity of the underlying hypokalemia or even lead to normal or high values.

Other manifestations of muscle dysfunction due to hypokalemia include:

● Respiratory muscle weakness, which can be severe enough to result in respiratory failure and death.

● Involvement of gastrointestinal muscles, resulting in ileus and its associated symptoms of distension, anorexia, nausea, and vomiting.

A variety of arrhythmias may be seen in patients with hypokalemia. These include premature atrial complex (PAC; also referred to a premature atrial beat, premature supraventricular complex, or premature supraventricular beat) and premature ventricular beats, sinus bradycardia, paroxysmal atrial or junctional tachycardia, atrioventricular block, and ventricular tachycardia or fibrillation [2]. Hypokalemia produces characteristic changes on the ECG although they are not seen in all patients. There is depression of the ST segment, decrease in the amplitude of the T wave, and an increase in the amplitude of U waves which occur at the end of the T wave (waveform 1). U waves are often seen in the lateral precordial leads V4 to V6. Hypokalemia also prolongs the QT interval [11-13]

There is a large interpatient variability in the serum potassium concentration that is associated with progression of ECG changes or arrhythmias. In a carefully controlled trial of thiazide therapy (hydrochlorothiazide 50 mg/day), there was a two-fold increase in ventricular arrhythmias (as detected by Holter monitoring) in the small proportion of patients in whom the serum potassium concentration fell to or below 3.0 mEq/L [14]. In addition, the presence of concomitant factors, such as coronary ischemia, digitalis, increased beta-adrenergic activity, and magnesium depletion, can promote arrhythmias; the last two of these cofactors can also lower the serum potassium concentration

Epinephrine released during a stress response (as with coronary ischemia) drives potassium into the cells, possibly worsening preexisting hypokalemia. A similar effect can be seen with bronchodilator therapy with a beta-adrenergic agonist.

Hypokalemia may be associated with magnesium depletion (due, for example, to diuretics or diarrhea), both of which promote the development of arrhythmias. Hypokalemia and hypomagnesemia are associated with an increased risk of torsades de pointes, particularly in patients treated with drugs that prolong the QT interval or those with a genetic predisposition to the long QT syndrome. In addition to its direct proarrhythmic effect, hypomagnesemia can increase urinary potassium losses and lower the serum potassium concentration.

Hypokalemia reduces insulin secretion, which may play an important role in thiazide-associated diabetes. However, worsening glucose tolerance is much less common in the era of low-dose thiazide therapy (eg, 12.5 to 25 mg of hydrochlorothiazide)

The neuromuscular and cardiac symptoms induced by hypokalemia are related to alterations in the generation of the action potential [2]. The ease of generating an action potential (called membrane excitability) is related both to the magnitude of the resting membrane potential and to the activation state of membrane sodium channels. Opening the sodium channels leads to the passive diffusion of extracellular sodium into the cells, which is the primary step in this process.

According to the Nernst equation, the resting membrane potential is related to the ratio of the intracellular to the extracellular potassium concentration. In skeletal muscle, a reduction in the serum (extracellular) potassium concentration will increase this ratio and therefore hyperpolarize the cell membrane (that is, make the resting potential more electronegative); this impairs the ability of the muscle to depolarize and contract, leading to weakness. However, in some cardiac cells (such as Purkinje fibers in the conducting system), hypokalemia causes K2P1 channels, which are normally selective for potassium, to transport sodium into the cells, causing depolarization [16,17]. This leads to increased membrane excitability and arrhythmias.

Hypokalemia also delays ventricular repolarization by inhibiting the activity of potassium channels responsible for this component of the cardiac electrical cycle [12]. (See "Reentry and the development of cardiac arrhythmias".)

In addition, hypokalemia causes ventricular arrhythmias through downregulation of cardiac Na-K-ATPase activity [18,19]. This produces an increase in intracellular sodium, which impedes removal of intracellular calcium by the Na-Ca exchanger, leading to intracellular calcium overload. The ensuing activation of calmodulin kinase II activity reduces repolarization reserve by activating late sodium and calcium currents [20]. This, in turn, predisposes the heart to early afterdepolarization-associated arrhythmias, such as Torsades de pointes and polymorphic ventricular tachycardia [20]

The assessment of the hypokalemic patient begins with evaluation of muscle strength and obtaining an electrocardiogram to assess the cardiac consequences of the hypokalemia, with particular attention to the QT interval. At serum potassium concentrations below 2.5 mEq/L, severe muscle weakness and/or marked electrocardiographic changes may be present and require immediate treatment

Telemetry or continuous ECG monitoring is indicated for hypokalemic patients with a prolonged QT, other ECG changes associated with hypokalemia, and/or underlying cardiac issues that predispose to arrhythmia in the setting of hypokalemia (digoxin toxicity, myocardial infarction, underlying long QT syndrome, etc)

The urgency of therapy depends upon the severity of hypokalemia, associated and/or comorbid conditions, and the rate of decline in serum potassium concentration

The risk of arrhythmia from hypokalemia is highest in older patients, patients with organic heart disease, and patients on digoxin or antiarrhythmic drugs [23].

Potassium replacement is the mainstay of therapy in hypokalemia. Such therapy is clearly warranted in patients with hypokalemia due to renal or gastrointestinal losses. It should also be considered when hypokalemia is due to redistribution of potassium from the extracellular fluid into the cells (eg, hypokalemic periodic paralysis, insulin therapy) if serious complications such as paralysis, rhabdomyolysis, or arrhythmias are present or imminent.

Hypomagnesemia and redistributive hypokalemia — The underlying cause of the hypokalemia should be identified as quickly as possible, particularly the presence of hypomagnesemia or redistributive hypokalemia:

Patients with hypokalemia may also have hypomagnesemia due to concurrent loss with diarrhea or diuretic therapy or, in patients with hypomagnesemia as the primary abnormality, renal potassium wasting [24,25]. Such patients can be refractory to potassium replacement alone [26]. Thus, measurement of serum magnesium should be considered in patients with hypokalemia and, if present, hypomagnesemia should be treated.

The risk of rebound hyperkalemia is particularly high in patients with hypokalemic or thyrotoxic periodic paralysis in whom rebound hyperkalemia has been described in 40 to 60 percent of treated attacks

When increased sympathetic tone is thought to play a major role, the administration of a nonspecific beta blocker, such as propranolol, should be considered. The greatest experience is with acute attacks of hypokalemic thyrotoxic periodic paralysis [31], although head injury and theophylline toxicity can also result in redistributive hypokalemia [32-35], presumably due to sympathetic activation and elevated epinephrine levels [36]. In such patients, high-dose oral propranolol or intravenous propranolol rapidly reverses the hypokalemia and paralysis seen in acute attacks, without rebound hyperkalemia

Estimation of the potassium deficit assumes that there is a normal distribution of potassium between the cells and the extracellular fluid. The most common settings in which this estimation does not apply is diabetic ketoacidosis or nonketotic hyperglycemia, and in redistributive causes of hypokalemia such as hypokalemic periodic paralysis.

Estimation of the potassium deficit and careful monitoring of the serum potassium helps to prevent hyperkalemia due to excessive supplementation. This is not an uncommon outcome in hospitalized patients since, in one report, one in six patients developed mild hyperkalemia following potassium administration for hypokalemia [38]. The risk of overcorrection is increased in patients with a reduced glomerular filtration rate.

In different studies, the serum potassium concentration fell by approximately 0.27 mEq/L for every 100 mEq reduction in total body potassium stores [3,37,39] and, in chronic hypokalemia, a potassium deficit of 200 to 400 mEq is required to lower the serum potassium concentration by 1 mEq/L [39]. However, these estimates are only an approximation of the amount of potassium replacement required to normalize the serum potassium concentration and careful monitoring is required

In diabetic ketoacidosis or a hyperosmolar hyperglycemic state (nonketotic hyperglycemia), hyperosmolality and insulin deficiency favor the movement of potassium out of cells. As a result, the serum potassium concentration at presentation may be normal or even elevated despite a marked potassium deficit due to urinary and, in some patients, gastrointestinal losses [40]. The initiation of insulin therapy and fluid replacement will lower the serum potassium toward the level appropriate for the potassium deficit. Potassium supplementation is usually begun once the serum potassium concentration is 4.5 mEq/L or lower.

Occasional patients with uncontrolled diabetes (eg, 6 percent in one study) have more marked potassium loss and are hypokalemic at presentation [41]. Such patients require aggressive potassium replacement (20 to 30 mEq/hour), which can be achieved by the addition of 40 to 60 mEq of potassium chloride to each liter of one-half isotonic saline. Since insulin will worsen the hypokalemia, insulin therapy should be delayed until the serum potassium is above 3.3 mEq/L to avoid possible complications of hypokalemia such as cardiac arrhythmias and respiratory muscle weakness.

Potassium bicarbonate or its precursors are preferred in patients with hypokalemia and metabolic acidosis (eg, renal tubular acidosis or diarrhea) [23,37]. Only potassium acetate is available for intravenous use.

Potassium phosphate should be considered only in the rarely seen patients with hypokalemia and hypophosphatemia, as might occur with proximal (type 2) renal tubular acidosis associated with Fanconi syndrome and phosphate wasting [37,42,43]

Potassium chloride is preferred in all other patients for two major reasons [1]:

• Patients with hypokalemia and metabolic alkalosis are often chloride depleted due, for example, to diuretic therapy or vomiting. In such patients, chloride depletion contributes to maintenance of the metabolic alkalosis by enhancing renal bicarbonate reabsorption and may contribute to potassium wasting as sodium is reabsorbed in exchange for secreted potassium rather than with chloride [3,44,45]. It has been estimated that administration of non-chloride-containing potassium salts in the presence of metabolic alkalosis results in the retention of only 40 percent as much potassium as the administration of potassium chloride [45]. (See "Pathogenesis of metabolic alkalosis", section on 'Chloride depletion' and "Treatment of metabolic alkalosis", section on 'Treatment'.)

• Potassium chloride raises the serum potassium concentration at a faster rate than potassium bicarbonate. Chloride is primarily an extracellular anion that does not enter cells to the same extent as bicarbonate, thereby promoting maintenance of the administered potassium in the extracellular fluid [46] In addition, potassium bicarbonate may partially offset the benefits of potassium administration by aggravating metabolic alkalosis, if present

Oral potassium chloride can be given in crystalline form (salt substitutes), as a liquid, or in a slow-release tablet or capsule. Salt substitutes contain 50 to 65 mEq per level teaspoon; they are safe, well tolerated, and much less expensive than the other preparations [47]. Liquid forms of potassium chloride are also inexpensive, but are often unpalatable. Nevertheless, they may be preferred in patients with an enteral feeding tube or who are unable to swallow tablets. Slow-release tablets are better tolerated, but they have been associated with gastrointestinal ulceration and bleeding, which have been ascribed to local accumulation of high concentrations of potassium [48]. The risk is relatively low, and even lower with microencapsulated preparations (eg, microK or Klor-Con) compared to wax matrix tablets [3]

Increasing the intake of potassium-rich foods, such as oranges and bananas (table 1), is less effective, in part because dietary potassium is predominantly in the form of potassium phosphate or potassium citrate which, as mentioned earlier in this section, results in the retention of only 40 percent as much potassium as potassium chloride [45]. In addition, the potassium concentration is relatively low in fruit (eg, approximately 2.2 mEq/inch [0.9 mEq/cm] in bananas) [49]. As a result, it would take two to three bananas to provide 40 mEq